rs72950039

Variant names:

• chr3-69763752-C-T
• rs72950039
• NM_001354604.2:c.104+24051C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001354604.2(MITF):​c.104+24051C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,358,386 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (140 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (92 hom.)
• Consequence: MITF NM_001354604.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.512
• Publications: 2 publications found

Genes affected

MITF (HGNC:7105): (melanocyte inducing transcription factor) The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]

MITF Gene-Disease associations (from GenCC):

• Tietz syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet
• Waardenburg syndrome type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Waardenburg syndrome type 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• melanoma, cutaneous malignant, susceptibility to, 8

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Waardenburg syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Waardenburg-Shah syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-69763752-C-T is Benign according to our data. Variant chr3-69763752-C-T is described in ClinVar as Benign. ClinVar VariationId is 1291113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354604.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	NM_001354604.2	MANE Select	c.104+24051C>T		intron	N/A	NP_001341533.1	O75030-1
	MITF	NM_001354605.2		c.104+24051C>T		intron	N/A	NP_001341534.1
	MITF	NM_198159.3		c.104+24051C>T		intron	N/A	NP_937802.1	O75030-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.104+24051C>T		intron	N/A	ENSP00000295600.8	O75030-1
	MITF	ENST00000956046.1		c.104+24051C>T		intron	N/A	ENSP00000626105.1
	MITF	ENST00000956043.1		c.104+24051C>T		intron	N/A	ENSP00000626102.1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3461 AN: 152198 Hom.: 139 Cov.: 33

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00214 AC: 2582 AN: 1206070 Hom.: 92 Cov.: 31 AF XY: 0.00191 AC XY: 1127 AN XY: 589146

African (AFR) AF: 0.0814 AC: 2149 AN: 26394

American (AMR) AF: 0.00409 AC: 104 AN: 25412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19884

East Asian (EAS) AF: 0.00 AC: 0 AN: 22718

South Asian (SAS) AF: 0.000314 AC: 23 AN: 73344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26784

Middle Eastern (MID) AF: 0.00105 AC: 5 AN: 4756

European-Non Finnish (NFE) AF: 0.0000667 AC: 64 AN: 959972

Other (OTH) AF: 0.00506 AC: 237 AN: 46806

GnomAD4 genome AF: 0.0228 AC: 3470 AN: 152316 Hom.: 140 Cov.: 33 AF XY: 0.0223 AC XY: 1664 AN XY: 74490

African (AFR) AF: 0.0796 AC: 3307 AN: 41554

American (AMR) AF: 0.00771 AC: 118 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68028

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0193 Hom.: 9

Bravo AF: 0.0262

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.47
PhyloP100		-0.51
PromoterAI		0.023	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72950039; hg19: chr3-69812903;